Regulation of T cell responses plays a primary role in determining the outcome of auto-immune disease, the development of tumor immunity, and graft survival following transplantation (Bluestone, et.al. Annu, Rev. Immunol. 1996, 14, 233-258.; Kuchroo, et. al. Crit. Rev. Immunol. 1998, 18, 389-418.; Guinan, et. al. N. Engl. J. Med. 1999, 340,1704-1714.; Abrams et. al. J. Exp. Med. 2000, 192, 681-694). These immune responses are controlled by the interaction of molecules on T cell and antigen presenting cell surfaces. Activation of T cells requires two signals, an antigen-specific signal delivered through T cell antigen receptor, and a second co-stimulatory signal. This co-stimulatory signal dictates the outcome for T cells through the binding of B7-1 and B7-2 expressed on antigen presenting cells to CD28 and CTLA-4 on T cells. CD28 engagement by B7-1 or B7-2 amplifies T cell receptor signaling and stimulates production of cytokines required for T-cell proliferation. On the other hand, CTLA-4 engagement by B7-1 or B7-2 down regulates the immune response (Allison, et. al. Nature 1992, 356, 607-609.; Bluestone, et. al. Immunity 1994, 1, 405-413.; Thompson, et. al. Science 1995, 270, 985-988). In experimental disease models, altering these co-stimulatory signals has profound effects on immunity. Blocking B7/CD28 interactions with monoclonal antibodies or soluble receptors results in immunosuppression and enhanced allograft survival, while B7/CTLA-4 blockade results in enhanced anti-tumor immune responses (Larsen, et. al. Nature 1996, 381, 434-438). Consequently, agents, such as small molecules, which act as inhibitors of cell-cell interactions may be useful in the development of effective immunomodulatory medicines.
Therefore, it is an object of this invention to provide compounds which are useful as immunotherapeutic agents in the treatment of transplant rejection, autoimmune disease or graft vs host disease.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of transplant rejection, autoimmune disease or graft vs host disease.
It is a feature of this invention that the compounds provided may be used to further study and elucidate the interactions of B7-1 with the CD28 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a compound of formula I: 
wherein
R1 and R2 are each independently H, C1-C10alkyl optionally substituted with one or more halogen, hydroxy, C1-C4alkoxy, CO2R6, CONR7R8, C3-C7cycloalkyl or optionally substituted phenyl groups, or
phenyl optionally substituted with one to three halogen, hydroxy, C1-C6haloalkyl, C1-C4alkoxy, CO2R9, NR10R11 or CN groups;
R3 is H, C1-C6alkyl optionally substituted with a phenyl, naphthyl or heteroaryl group each group optionally substituted with one to three C1-C6alkyl, C1-C6haloalkyl, C1-C4alkoxy, hydroxy, CHO, NO2, CN, CO2R12 or NR13R14 groups,
phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, CONR15R16, SO2NR15R16, CO2R17, NR18R19 or CH2CO2R20 groups,
naphthyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, CO2R17, NR18R19 or CH2CO2R20 groups,
C5-C7cycloheteroalkyl optionally substituted with one to three halogen, NO2, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C4alkoxy, CO2R17 or NR18R19 groups, or
heteroaryl optionally substituted with one to three halogen, NO2, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C4alkoxy, CO2R17 or NR18R19 groups;
R4 is phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR26, SO2NR21R22, CO2R23 or NR24R25 groups,
cycloheteroalkyl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR26, SO2NR21,R22, CO2R23 or NR24R25 groups, or
heteroaryl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR26, SO2NR21R22, CO2R23 or NR24R25 groups;
R5 is H, C1-C3alkyl or haloalkyl;
R6, R9, R12, R17, R20, R26 and R27 are each independently H or a C1-C6alkyl, C3-C7 cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted;
n is 0 or an integer of 1 or 2;
R7, R8, R10, R11, R13, R14, R18, R19, R21, R22, R24 and R25 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted or each of R7 and R8 or R10 and R11 or R13 and R14 or R18 and R19 or R21 and R22 or R24 and R25 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; and
R15 and R16 are each independently H, NH2, CH2CH2OCH2CH2OCH2CH2NH2 or a C1-C6alkyl group optionally substituted with one or two CN, OR5, NR13R14, CO2R17 or C3-C7cycloalkyl group;
phenyl optionally substituted with one or two halogen, OR5, CN, NR13R14, CO2R17, COR27, an optionally substituted C1-C8alkyl group or an optionally substituted C2-C6alkenyl group;
benzyl optionally substituted with one or two halogen, OR5, COR27 or a C1-C6alkyl group optionally substituted with one OR5 or
pyridinyl optionally substituted with one or two halogen, OR5, NR13R14 or CO2R17 groups or
R15 and R16 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, N or S; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the immunotherapeutic treatment of transplant rejection, autoimmune disease or graft vs host disease.